Process for the preparation of tetrahydropyrimidoisoindolols

ABSTRACT

This invention is concerned with tetrahydropyrimidinyl phenyl carbonyl acid addition salts, imidazolinyl phenyl carbonyl acid addition salts, dihydroimidazoisoindolols, tetrahydropyrimidoisoindolols, and tetrahydropyrimidoisoindolol acid addition salts which are all pharmacologically efficacious as anti-depressants. The tetrahydropyrimidinyl phenyl carbonyl acid addition salts, the tetrahydropyrimidoisoindolols and the tetrahydropyrimidoisoindolol acid addition salts are also efficacious as diuretics while the imidazolinyl phenyl carbonyl acid addition salts and the dihydroimidazoisoindolols are efficacious as anorexiants. This invention is also concerned with several processes for the preparation of these compounds.

[ 1 Aug. 5, 1975 PROCESS FOR THE PREPARATION OF TETRAHYDROPYRIMIDOISOINDOLOLS [75] Inventor: Theodore S. Sulkowski, Wayne, Pa.

[73] Assignee: American Home Products Corporation, New York. N.Y.

[22] Filed: Sept. 5, 1973 [211 App]. No.: 394,615

Related US. Application Data [60] Division of Ser. No. 757.792, Sept. 5. 1968, Pat. No. 3.763.178. which is a continuation-in-part of Ser. Nos. 622,918. March 14, 1967, abandoned, and Ser. No. 576,833, Sept. 2, l966, abandoned. and Ser. No. 487.587. Sept. 15. 1965. abandoned.

[52] US. Cl... 260/256.4 F; 260/251 A; 260/25l R; 260/256.5 R; 260/256.4 H; 260/309.6; 260/326.ll

[5 1] Int. Cl. C07D 239/06; CO7D 487/14 [58] Field of Search 260/251 A, 251 R, 256.4 F, 260/256.5 R

[56] References Cited UNITED STATES PATENTS 3.444.181 5/1969 Houlihan zoo/309.6

OTHER PUBLICATIONS Fieser et al., Advanced Organic Chemistry." Reinhold Publishing Corp., N.Y., (1961). P- l 144.

Primary Evaminer-Donald G. Daus Assistant Eruminer-Diana G. Rivers Attorney, Agent, or FirmStephen Venetianer [57] ABSTRACT This invention is concerned with tetrahydropyrimidinyl phenyl carbonyl acid addition salts, imidazolinyl phenyl carbonyl acid addition salts, dihydroimidazoisoindolols, tetrahydropyrimidoisoindolols, and tetrahydropyrimidoisoindolol acid addition salts which are all pharmacologically efficacious as antidepressants. The tetrahydropyrimidinyl phenyl carbonyl acid addition salts, the tetrahydropyrimidoisoindolols and the tetrahydropyrimidoisoindolol acid addition salts are also efficacious as diuretics while the imidazolinyl phenyl carbonyl acid addition salts and the dihydroimidazoisoindolols are efficacious as anorexiants. This invention is also concerned with several processes for the preparation of these compounds.

2 Claims, No Drawings PROCESS FOR THE PREPARATION OF TETRAHYDROPYRIMIDOISOINDOLOLS This is a division of application Ser. No. 757,792, filed Sept. 5. |9.68.-now US. Pat. No. 3.763.178. which application is a continuation-inpart of US Pat. applications. Ser. No. 622.918. entitled Tetrahydropyrimidinyl Phenyl Carbonyl and lmidazolinyl Phenyl Carbonyl Compounds. filed Mar. 14. 1967; Ser. No. 622.93 1 entitled Process for the Preparation of lmidazolinyl Phenyl Carbonyl Compounds. filed Mar. 14. 1967; Ser. No. 576.833. entitled 2-(3- Aminopropyl) lsoindoles and Related Compounds. filed Sept. 2. 1966: and Ser. No. 487.587. entitled l2.3.4.6.lb-Hexahydropyrimido[2.l-a] lsoindol- 6-Ones and Related Compounds." filled Sept. 15. 1965 and all now abandoned.

This invention relates to bicylic and tricyclic nitrogen containing compounds as well as to novel methods for their preparation. In particular, the present invention is concerned with tetrahydropyrimidinyl phenyl carbonyl acid addition salts, tetrahydropyrimidoisoindolols and tetrahydropyrimidoisoindolol acid addition salts which in standard and accepted pharmacological tests have demonstrated both anti-depressant and diuretic activities. Further. it is concerned with imidazolingly phenyl carbonyl acid addition salts and dihydroimidazoisoina dolols which in standard and accepted pharmacological tests have demonstrated both anti-depressant and anorexiant activities.

The new and novel compounds which are included within the scope of this invention are represented by the following formulae: i

wherein R and R, are selected from the group consisting of hydrogen, lower alkyl, phen(lowcr)alkyl,alkyl,

2 hydrogen when R and R are dissimilarand when R and R are the same they are both selected from the group consisting ofhydrogen, halogen, lower alkyl and lower alkoxy; R is selected from the group consisting of phenyl, monohalophenyl, mono(lower)alkylphenyl, di(lower)alkylphenyl, trifluoromethylphenyl, mono(lower)alkoxyphenyl, di'(lower)alkoxyphenyl, thienyl, pyridyl, furyl and tetrahydro-2-naphthyl; n is an integer from 1 to 2; and HX is a pharmacologically acceptable acid addition salt. As employed herein the terms lower alkyl, lower alkoxy" and the like are meant to include both branched and straight chain moieties containing from one to about six carbon atoms.

The new' and novel compounds of this invention which are represented by structural formula (I) wherein n is 1 are called Imidazolinyl Phenyl Carbonyl Acid Addition Salts. Typical examples thereof are: 2(2-imidazolin-2-yl)benzophenone hydrochloride and 4'-ehloro-2-(2-imidazolin-2-yl)benzophenone hydrochloride.Alternatively, those compounds of structural formula (I) wherein n is 2 are named: Tetrahydropyrimidinyl Phenyl Carbonyl Acid Addition Salts, such 'as, 2-(3,4,5,6-tetrahydro-2-pyrimidinyl)-4- methylbutyrophenone hydrochloride and 2-phenyl- 2-('-3,4,5,6-tetrahydro-2-pyrimidinyl)aeetophenone hydrochloride The new and novel compounds of this invention which are depicted; by structural formula ([1) wherein n is 1 are designated "Dihydroimidazoisoindolols, for

example, 2,3-dihydro-5-phenyl-5H-imidazo[2,1-a

N and ]isoindol-5-ol and 5-(4-chlorophenyl)-2,3-dihydro5H- imidazol2, l -a lisoindol- 5-01. Alternatively, these compounds of structural formula (11) wherein n is 2 are called "Tetrahydropyrimidoisoindolols", such as, 6-(4- chlorophenyl )-2,3 ,4,6-tetrahydropyrimido[ 2, l-a lisoindol-6-ol and 2,3,4,6-tetrahydro-6- pheny1pyrimidol2,1-a ]isoindol-6-ol.

The new and novel compounds of this invention which are represented by structural formula (111) are named "Tetrahydropyrimidoisoindolol Acid Addition dihalophenyl,

(A) wherein R R and R, are defined as above. Various oxidation processes will readily suggest themselves to those skilled in the art. For example, the particular 2-(3-aminopropyl)isoindole (A) may be dissolved in a reaction-inert solvent, e.g. an alkanol, and purged with oxygen or air until the oxidation is complete. Alternasium chlorate, or potassium permanganate. The oxidation reaction may be conducted in any suitable reaction-inert solvent. Many such solvents will readily suggest themselves to one skilled in the art of organic chemistry.

When the aforesaid oxidation is complete, the product is separated by standard recovery methods, such as, concentration. filtration and crystallization. The ter- 10 tahydropyrimidoisoindolols (B) may then be recrystallizcd from an appropriate solvent, such as dimethylformamide and dimethylacetamide.

In accord with the new and novel second process of the present invention, the dihydroimidazoisoindolols of this invention may be synthesized by the following schematic sequence of reactions:

2 2 NCH2CH2NH R3 R CH R N N 2 H s0 R NSO R R 2 4 2 6 I R4 R4 (3) (4) tively, the oxidation may be accomplished by contacting the 2-( 3-aminopropyl) isoindolc solution with an oxidzing agent, such as potassium dichromate, potaswherein R R and R, are defined as above, R is aryl and alkyl, for example: lower alkyl, phenyl, monohalophenyl, dihalophcnyl, mono(lowcr)alkylphenyl, di(lower)alkylphcnyl and alkoxyphenyl, and X is the anion portion of a mineral acid. The rearrangement of a tetrahydroimidazoisoindolone of formula 1 is effected by contacting the particular compound (1) with a mineral acid. This reaction may be accelerated by heating and stirring the reaction mixture until the precipitation of the 2-(arninoethyl)-3- hydroxyphthalimidine mineral acid addition salt, as designated in formula (2), is complete. The phthalimidine (2) is separated by filtration or decantation and either recrystallized from a suitable solvent, such as water, a lower alkanol and dioxan, or admixed directly with a substantially equimolar quantity of an aryl or alkyl sulfonyl halide in pyridine. The reaction mixture is then heated to a temperature from about 80C. to about 115C. for a period from about two hours to about ten hours. Preferably, this reaction is conducted at the reflux temperature of the reaction mixture for a period of about two hours. After the above reaction is complete, the product of sulfonyltetrahydroimidazoisoindolone (3) is recovered by customary isolation procedures.

The above prepared sulfonyltetrahydroimidazoisoindolone (3) may be hydrolyzed and rearranged by admixture with from about 80 to about 100 percent sulfuric acid. The product of this hydrolysis, the sulfate salt of an imidazolinyl phenyl carbonyl compound, as shown in formula (4) which may be recovered as such by conventional means. Alternatively, the reaction mixture is neutralized by the addition of a base and the resulting precipitate recrystallized from an appropriate organic solvent such as lower alkanol, dioxan, dimethylformamide and dimethylacetamide to afford an appropriate dihydroimidazoisoindolol (5).

As a new and novel alternative to the second process of the present invention, it has been found that the dihydroimidazoisoindolols of this invention may also be prepared by directly reacting a tetrahydroimidazoisoindolone l with an aryl or alkyl sulfonyl halide under the above-described reaction conditions to afford an appropriate sulfonyltetrahydroimidazoisoindolone (3). Thereafter, this compound (3) is further reacted as hcreinbefore described to yield an imidazolinylphenyl carbonyl sulfate salt (4) which may then be neutralized to afford a dihydroimidazoisoindolol (5).

As a further alternative to the second process of the present invention, it should be noted that the 2- (aminoethyl)-3-hydroxyphthalimidine (2) intermediates can also be prepared by the condensation of an acid chloride of an o-carbonyl benzoic acid with ethylene diaminc as described by Sulkowski et a] in J. Org. Chem. 32, 2180 (1967).

In accord with the new and novel third process of the present invention, some of the dihydroimidazoisoindolols of this invention may be prepared by the procedure which is exemplified by the following reaction 6 yphenyl, di(lower)alkylphenyl, di(lower)alkoxyphenyl, aminophenyl, trifluoromethylphenyl, monohalophenyl, dihalophenyl. furyl, thienyl and naphthyl; R is selected .from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy; R is hydrogen when R and R are dissimilar and when R and R are the same they are both selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy.

The oxidation reaction is effected by contacting an appropriate hexahydrobenzodiazocine (a) with an oxidizing agent in a reaction-inert solvent at a temperature from about 20C. to about C. for a period of about /2 to about 4 hours. Preferably, this reaction is conducted by contacting an aqueous solution of a hexahydrobenzodiazocine salt with a potassium permanganate solution at room temperature for about one hour. Many other oxidizing agents and reaction-inert solvents which may be employed in this reaction will readily suggest themselves to those skilled in the art. In this regard, excellent results can be obtained when potassium dichromate and potassium chlorate are employed as the oxidizing agents. By reaction-inert solvent as employed herein is meant a solvent which will dissolve the hexahydrobenzodiazocine and not interfere with the oxidation reaction, such as, water while acetone and methyl ethyl ketone may be employed as solvents when potassium permanganateis employed as the oxidizing agent.

When the oxidation reaction is complete, the corresponding dihydroimidazoisoindolol (b) may be separated and recovered by routine means, for example, precipitating the product by the addition of a base and then separating it by decantation or filtration. The time and temperature ranges employed in the aforesaid reactions are not critical but simply represent the most convenient range consistent with carrying out these reactions in a minimum of time without undue difficulty. Thus reaction temperatures appreciably below these can be used, but their use considerably extends the reaction time. Similarly, reaction temperatures higher than those mentioned can be employed with a concomitant decrease in reaction time. The 2-(3 aminopropyl)isoindoles (A) employed as starting materials in the first above described process for the preparation of the tetrahydropyrimidoisoindolol compounds (B) of this invention are known compounds which are described in co-pending U.S. Pat. application, Ser. No. 622,917, entitled isoindoles, Isoindolines and Related Compounds, filed on Mar. 14, 1967, by Theodore S. Sulkowski which is a continuation-inpart of U.S. Pat. applications, Ser. No. 576,833, entitled 2-(3-Aminopropyl)lsoindoles and Related Compounds, filed Sept. 2, 1966 and Ser. No. 487,587, entitled 1,2,3 ,4,6, l0b-Hexahydropyrimido[ 2, l a]Isoindol-6-Ones,filed Sept. 15, 1965 and now abandoned. The tetrahydroimidazoisoindolones'( l and the scheme: hexahydrobenzodiazocines (a) which are respectively N H l r: R 8 R 8 R OH R N 9 R (a) wherein R is selected from the group consisting of lower alkyl, phenyl, lower alkylphenyl, lower alkoxemployed as starting materials in the second and third above described process for the preparation of the 7 dihydroimidazoisoindolols of this invention are known compounds which are described in co-pending U.S. Pat. application, Ser. No. 609,779, entitled Benzodiazocines, filed on Jan. 17, 1967, by Theodore S. Sulkowski, which is a continuation-in-part of U.S. Pat. applications, Ser. No. 554,672, entitled Benzodiazocines", filed on June'2, 1966; Ser. No. 444,050, entitled Substituted 3,4-Dihydro-6-Aryl-2,5- Benzodiazocin-l(2H)-Ones and Related Compounds," filed on Mar. 30, 1965 and now abandoned; and Ser. No. 272,216, entitled Substituted 3,4-Dihydro-6- Aryl-2,5-Benzodiazocinl(2H)-Ones and Related Compounds, filed on Apr. 11, 1963 and now abandoned. The aryl or alkyl sulfonyl chlorides used in this latter process are well known chemicals which are commerically available or may easily be prepared by well known chemical procedures.

The tetrahydropyrimidoisoindolols (B) of the present invention were at first thought to be Hexahydropyrimidoisoindolones" and were so described in the first prior filed parent application (U.S. Ser. No. 487,587). Subsequently, these compounds were reexamined and then thought to be Tetrahydropyrimidinyl Phenyl Carbonyl Compounds and were so defined in the following two subsequently filed parent applications (U.S. Ser. Nos. 576,833 and 622,918). It has now been concluded, based on the nature of the starting materials; the mode of synthesis; the elemental analysis; and the ultra violet and infra red spcctrographic analyses, that all the solid bases prepared by the first process of this invention are Tetrahydropyrimidoisoindolols (B). Further, since these nitrogen containing tetrahydropyrimidoisoindolols are basic in nature they will react with pharmacologically acceptable acids to form acid addition salts. Such acids are well known in the art, for example, hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, acetic, laction, citric, tartaric, maleic, gluconic, benzenesulfonic, toluenesulfonic, methylsulfonic, ethylsulfonic acids and the like. These salts may be prepared by procedures commonly employed in the art, for example, reacting the compound with an equivalent of the selected acid in aqueous solution and concentration of the solution. Other known procedures may also be employed, e.g., the procedure of Example Vlll.

The ultra violet spectrographic analyses of the tetrahydropyrimidoisoindolols (B) of this invention and their acid addition salts which are substitued in the 6- position with an aromatic group, e.g. phenyl, monohalophenyl dihalophenyl, mono(lower)alkylphenyl, di(lower)alkylphenyl, trifluoromethylphenyl, mono(lower)alkoxyphenyl, di(lower) alkoxyphenyl, thienyl, pyridyl, furyl and tetrahydro-Z-naphthyl, demonstrate an absence of absorption in the 250 my. region indicating that both the bases and salts possess these tetrahydropyrimidoisoindol structures in solution. A]- ternatively, ultra violet analyses of neutral and acidic solutions of these tetrahydropyrimidoisoindolols (B) and their acid addition salts which are unsubstituted, e.g. hydrogen or substituted in the 6-position with an aliphatic or aralkyl group, e.g. lower alkyl and phen(- lower)alkyl demonstrate absorption in the 235240 mp. region indicating that their structures in solution are predominately the tetrahydropyrimidinyl phenyl carbonyl compounds of the structure:

R wherein R and R are defined as above and R is hydrogen, lower alkyl and phen(lower) alkyl. Further, the infra red spcctrographic analyses of these latter compounds determined by the procedure of Hofmann et al, Analyt. Chem, Vol 39, pg. 406 (1967) also indicates that the solid acid addition salts thereof also exist in the above shown tetrahydropyrimidinyl phenyl carbonyl forms.

The dihydroimidazoisoindolols (5) of the present invention were first thought to be Tetrahydroimidazoindolones and were so described in the first prior filed parent application. Subsequently, these compounds were re-examined and then thought to be Imidazolinyl Phenyl Carbonyl Compounds and were so defined in the following three subsequently filed parent applications U.S. Ser. Nos. 576,833, 622,931 and 622,918). It has now been concluded, based on the nature of the starting materials; mode of synthesis; the elemental analysis; and ultra violet and infra red analyses, that all solid bases prepared by the second and third process of this invention are Dihydroimidazoisoindolols" (5 Further, since these nitrogen containing dihydroimidazoisoindolols are basic in nature they also will react with pharmacologically acceptable acids as described above to form acid addition salts.

The ultra violet spcctrographic analyses of the dihydroimidazoisoindolols (5) of this invention in neutral solution demonstrate an absence of absorption in the 250 mu region indicating that these bases also possess these dihydroimidazoisoindolol structures when they are dissolved in a non-acidic solution. Alternatively, the ultra violet analyses of acid solution of these bases and the neutral solutions of their acid addition salts demonstrate absorption in 250 mu region indicating that they are imidazolinyl phenyl carbonyl compounds in solution of the structure:

R3 CzO where R R and R, are defined as above. The infra red spcctrographic analyses of these compounds also indicates that the solid bases are dihydroimidazoisoindolols while their corresponding solid acid addition salts exist in the above shown imidazolinyl phenyl carbonyl forms.

The tetrahydropyrimidinyl phenyl carbonyl said addition salts (formula I where n is 2); the tetrahydropyrimidoisiondolols (formula 11 where n is 2); and the tetrahydropyrimidoisoindolol acid addition salts (formula III) of the present invention have been found to possess valuable pharmacological activity. More particularly, these compounds have exhibitedm'tility, in standard pharmacological tests asantidepressant and diuretic agents. In the pharmacological evaluation of'the antidepressant property of thesecompounds (l; n=2'; ll, 113 2; and Ill), the in vivo anti-depressant:activit y is'evaluatedby the procedure described byRubin et alsin J.P.E.T.' 1'20, 125 1957). When tested bythis procedure,=these compounds demonstrate useful anti-depressant activity, e.g. having mood elevating properties as psychic en'ergizers, when they are administered'o'ra-lly to mice in a dosage range from about i to about 100 mg./kilo of animal body weight. Furtherfthin vivo diuretic activity of these compounds (I, n,=2; ll, n'f'2;..and lIl). is evaluated by the procedure described by Lipschitz et al, in J. Pharmacol. 79, 97..( l943):1when tested by this procedure these compounds demonstrateuseful diuretic activity when they are administered-legally to rats in a dosage range from about"i25rt:o.:about 25? mg./kilo of animal body weight. .1

The imidazolinyl phenyl carbonyl acid addition salts (formula I where n is l) and the' dihyd-roimidazoi'soindolols (formula [I where n is l of the present invention have also been found to possessvaluablepharmacological activity. In particular,-these compounds have exhibited utility, in standard pharmacological tests, as anti-depressant and anorexiant ageritsz' a" in the pharmacological evaluation of t'he antidepressant property of these compounds-hvi l and ll, n=l the in vivo anti-depressant activityis also evaluated by the procedure described by Rubin etgalfiin J.P;E.T. 120, 125 1957 When tested by this-procedure thesecompounds demonstrate useful anti-depressant. activity, e.g. having mood elevating properties as psychic energizers, when they are administered orally to mice in a dosage range from about l to'about mg./kilo of animal body weight. Furtherythein vivo anorexiant activity of these compounds-"(1, n =l and ll, n=l e.g. appetite suppressant effects is' 'e'valuated"'by-=the following Procedure: v

Male Charles River rats .betwe'en -1;20.and' -l 40. grams are trained to drink sweetened condensed milk from a graduated drinking t-ube-LAfter 'a short leaming period the animals are placed on a routine of wat'er ad lib for 24 hours, standard laboratory chow fOl'-'.22 hours and sweetened condensed milk for 2 hours. The volume of milk consumed is measured at onehalf-houras'well as 2 hours and the animals are weighed-daily. This schedule is maintained 5" days a weekjover' aperiod'ofseveral months. Trials are runon'the sameday each v'veek and changes in milk consumed;arid .-2.4} hour weight-changes are compared to the average of the 2 days before the test compound is administered Animals'arq tested as groups of six and one group is given saline each week to serve as controls. The testjcompounjdsare usually administered intraperitoneally in saline and[or orally in water. 1

The imidazolinyl phenyl carbonyl acid addition salts and the dihydroimidazoisoindololspf,thisipYgttjon in the above test procedure when administered orally to rats at a dose of mg./kg induce a decrease in food consumption of about 40 percent in :thc first half hour and about percent in: 2*,hQurs witlra $PQQPKTQEQ181 average weight loss of about one-half -gragnlanimal in 24 hours. whe admini'ster 'ed intr'aperitoneally at a dose of 10'mg. /kg., tliese compounds n l and,

n=l induce a decrease in food consumption of about eighty percent in the first half hour and about 65 percent in 2 hours with a concurrent total 24 hour average weight-loss of about 7 /2 grams/animal.

when the-tetrahydropyrimidinyl phenyl carbonyl acid addition salts; the tetrahydropyrimidoisoindolols and the 1'tetrahydropyrimidoisoindolol acid addition salts ofthis invention are employed as anti-depressant ,and .diureticagents and when the imidazolinyl phenyl carbonyl acid addition salts and the dihy- .droimidazoisoindolols of this invention are employed as anti-depressant and anorexiant agents, they may be administered to mammals, e.g. mice, rats, rabbits, dogs, cats, monkeys, etc. alone or in combination with pharmacologically acceptable carriers, the proportion of whichis determined by the solubility and chemical nature of the compound, chosen route of administration and, standard biological practice. For example, they may be administered orally in the solid form containing such excipients as starch, milk sugar, certain types of clay and so forth. They may also be administered orally in the form of solutions or they may be injected parenterally. For pare r iteral administration they may be used -in-the form of a sterile solution containing other solutes, forexample, enough saline or glucose to make the solution isotonic.

The dosage of the compounds of this invention will vary with the form of administration and the particular compound chosen. Furthermore, it will vary with the I The following examples are given by way of illustration and are not to be construed as limitations of this invention,,many variations of which are possible without departing from the scope and spirit thereof.

EXAMPLE 1 The v v 2-(3-aminopropyl)-l-(4- chlorophenyhisoindole, hydrochloride (2 grns.) is dis.- .solved i n water and neutralized with a sodium carbonatesolutiom The regenerated base is extracted with ethyl acetate, dried over magnesium sulfate and evaporatedtosdryness. The residue is dissolved in 250 ml. of ethanol and air is bubbled through the solution for 48 hours. The precipitated white crystalline solid is separated by filtration and upon recrystallization from dimethylformamide there is obtained 6-( 4- chlorophenyl )-2,3 ,4,6-tetrahydropyrimido[2,1- a]isoindol-6-ol, m.p. 2746C. dec., which is insoluble in water'and soluble in dimethylacetamide.

Analysis: Ultra Violet Absorption ETOH) max. .224 my. '(e=23,000), infl. 243 mp. (e=l2,000), max. 26] mz ,.(e=3,800); Ultra Violet Absorption (pH 1) 'max. 223 my. (e=2l,l00), infl. 243 mp. (e=l4,200),.

max:,2 6 7 mp.(=3,800); Infra. Red Absorption (KBr) 1652 cm, 24003000 cm.

The above prepared tetrahydropyrimidoisoindolol is dissolved in ethanol'and admixed with an aqueous solution containing an equivalent amount of hydrochloric acid. The mixture is stirred for 10 minutes and the solvent removed by evaporation. In this manner, is obtained 6-(4-chlorophenyl)-2,3.4,6- tetrahydropyrimido[2, 1 -a lisoindol-6-ol hydrochloride. m.p. 2324C., as a white crystalline solid, which is soluble in hot water.

Analysis: Ultra Violet Absorption (95% ETOH) max. 224 my. (e=23,000), infl. 243 mp. (e=l4,000)', infl. 268 mp. (e=3,800); Infra Red Absorption (KBr) l675cm, 2600-3300 cm.

Calcd for C, H, .,ClN O.HCl: C, 60.91; H, 4.81; N, 8.36; CI, 21.16. Found: C, 60.91; H, 5.06; N, 8.31;Cl,

EXAMPLE II The procedure of Example I is repeated reacting an appropriate 2-(3-aminopropyl)isoindole with an oxidizing agent, e.g. potassium dichromatc, potassium chlorate and hydrogen peroxide to afford the hereinafter listed products:

2-( 3-AMINOPROPYL) PRODUCTS ISOINDOLES 2-( 3-aminopropyl )-6-bromol 8-bromo-2,3,4,6-tetrahydro- (4-tolyl )isoindole 6-(4-tolyl)pyrimido[2,141]

isoindol-6-ol 2-( 3-aminopropyl )-5-methyll 2,3,4,6-tetrahydro-9- methyl-6-propylpyrimido [2, l -a ]isoindol-6-ol 2-( 3-aminopropyl )-4-iodoiso- 2,3,4,6-tetrahydrol indole iodopyrimidol 2, l -a lisoindol 2(3-aminopropyl)- 1-(4-bromo- 8,9-dibromo-6-( 4-bromophenyl ,(i-dibromoisoindole phenyl )-2,3,4.6-tetrahydropyrimido[ 2, 1 -a]isoindolpropylisoindole 2,3,4,6-tetrahydro-6-( 2,4- dimethoxyphenyl )pyrimido [2,1-alisoindol-6-ol 2-( 3-uminopropy1)-1-(2,4- dimethoxyphcnyl )isoindole EXAMPLE III 1 phenylisoindole is dissolved in 200 ml. of ethanol and oxygen is bubbled through the solution for 48 hours, The precipitated solid is separated by filtration and on recrystallization from dimethylformamide there is ob tained 2,3 ,4,6-tetrahydro-6-phenylpyrimidol 2 ,1 alisoindo1-6-ol, m.p. 2557C. dec., as white prisms which is insoluble in water and slightly soluble in hot dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH) max. 233 mp. (e=14,000), max. 268 mp. (e-4,000), infl. 271 my. (e=3,000); Ultra Violet Absorption (pH 1) max, 239 mp. (=14,900), infl. 271 mp. (e=3,000); Infra Red Absorption (KBr) 1650 cm", 2300-3000 cm".

Calcd for c n w o. C, 77.25; H, 6.10; N, 10.60. Found: C, 77.36; H, 60.5; N, 10.51. The above reaction is repeated in anhydrous diisopropyl ether at 60C. for 2 hours with similar results. In a similar manner, starting with l0b-(3,4- dichlorophenyl)-1,2,3,4,6,10b-hexahydropyrimidolZ,l-a]isoindol-6-one there is obtained 6- EXAMPLE 1v 2-( 3-Aminopropyl 1 4-bromophenyl )isoindole (4.0 gms.) is dissolved in 100 ml. of ethanol and oxidized by bubbling oxvgen through the solution for 36 hours.'The precipitated solid is separated by decantation and recrystallized from dimethylformamide. In this manner. is obtained 6-(4-bromophenyl)-2,3,4,6- tetrahydropyrimido 2, l -a isoindol6-ol, m .p. 2789C. dec., as a white crystalline solid which is insoluble in water and slightly solublein dimethylacetamide.

Analysis: Ultra Violet Absorption ETOH) max. 228 mp. (e=22,500), max. 267 mp. (e=4,300); Ultra Violet Absorption (pH 1) max. 229 mp. (e -21,500), max. 267 mp. (e=4,300); Infra Red Absorption (KBr) 1645 cm, 2300-2900 cm.

Caled for C H BrN O: C, 59.48; H, 4.41; N, 8.16.

Found: C, 59.51; H, 4.36; N, 8.26.

Similarly, utilizing anhydrous ethylene glycol dimethyl ether as the solvent, 6-(2,4-dibromophenyl)- 2 ,3 ,4,6-tetrahydropyrimido[2,1-a]isoindol-6-ol is synthesized. i

, EXAMPLE v 2-(3-Aminopropyl)-1-(5',6,7',8'-tetrahydro-2'- naphthyl)isoindole (3.0 gms.) is dissolvedin 250 m1. of benzene and oxidized by bubbling oxygen through the solution for 60 hours. The precipitate is separated by filtration and recrystallized from dimethylacetamide. In this manner, is obtained 6-(5,6,7,8-tetrahydro-2- naphthyl )-2,3 ,4,6-tetrahydropyrimido[2,1-a]isoindol- 6-01, m.p. 253-5C. dec., as a white crystalline solid which is insoluble in water and soluble in hot dimethylacetamide. t

Analysis: Ultra'Violet Absorption (95% ETOH) infl. 230 mp (e=10,000), infl'; 245 mp. (6=9,200), max. 270 my (e=3,200); Ultra Violet Absorption (pHl infl. 230 mp (e=10,900), infl. 245 mp, (e=l0,000), max. 270 my. (e=3,200); Infra Red Absorption (KBr) 1655 cm, 2300-3000 cm.

Cale'd for C ,H N O: C, 79.21; H, 6.96; N, 8.80. Found: C, 78.96; H, 7.15; N, 8.95. i

In a similar manner, 6-(4-trifluoromethylphenyl)- 2,3,4,6-tetrahydropyrimido[ 2, l -a]isoindol-6-ol; 6-( 2- trifluoromethylphcnyl)-2,3,4,6- tetrahydropyrirhidolZ,l-alisoindol-6-o1; and 6-fury1- 2 ,3 ,4,6-tctrahydropyrimido[ 2, l -'a]isoindol-6-ol are produced. Y

, EXAMPLE VI Repeating the procedure of Exampl'e'V but starting with 2-( 3-aminopropyl)- l'methylisoindole, there is obtained 2,3,4,6-tetrahydro--methylpyrimidol2,1- alisoindol-6-ol, m.p. l99-201C., as a'white crystalzine solid which is insoluble in water and soluble in dimethylacetamidc.

Analysis: Ultra Violet Absorption (95% ETOH) max. 236 mp. (e=12,600), infl. 265 mp. (e -4,100); Ultra Violet Absorption (pH 1) max. 239.5 mp. (e=14,200), infl. 265 mp. (e=4,l); Infra Red Absorption (KBr), 1640 cm, 2300-3000 cm; Infra Red Absorption of the in situ hydrochloride salt by the procedure of Hofmann et a1, Analyt. Chem. Vol. 39, pg. 406 (1967) (KBr) 1670 cm, 1647 cm, 2600-3100 cm.

Calcd for C H N O: C, 71.26; H, 6.98 N, 13.87. Found: C. 71.30: H.690: N. 13.63

In a similar manner, the following compounds are prepared:

2,3,4,6-Tetrahydropyrimido[2,l-alisoindol-6-ol, m.p. 205-7C., as a white crystalline sold which is insoluble in water and slightly soluble in dimethylacetamidc.

Analysis: Ultra Violet Absorption (95% ETOH) max. 235 mu (e=l2,400), infl. 266.5 mp. (e=3,650); Ultra Violet Absorption (pH 1) max. 240 m,u.'(e=l0,800), infl. 266.5 my. (s=3,650); Infra Red Absorption (KBr) 1640 cm, 2300-3000 cm, Infra Red Absorption of the in situ hydrochloride by the above-identified procedure (KBr) 1670 cm, 2600-3100 cm".

Calcd for C H N O: C, 70.18; H, 6.42; N, 14.88. Found: C, 69.92; H, 6.47; N, 14.71.

6-Benzyl2,3 ,4,6-tetrahydropyrimido[ 2, l-a]isoindol- 6 1, m.p. 233-5C. dec., as a white crystalline solid which is insoluble in waterv Analysis: Ultra Violet Absorption (95% ETOH) max. 235 mu (6 1 1,700), infl. 269 my. (e=3,900); Ultra Violet Absorption (pH lmax. 240 mp. (e=l2,900), infl. 269 mu (e=3,900); Infra Red Absorption (KBr) 1645 cm, 2300-3000 cm"; Infra Red Absorption of the in Z-(S-AMINOPROPYL) PHENYLISOINDOLES situ hydrochloride by the above-identified procedure (KBr) 1665 cm, 2600-3100 cm.

vCalcd for c,,,H,,,N o: C, 77.66; H, 6.52; N, 10.07. Found: C, 77.67; H, 6.41; N, 9.77.

6-Butyl-2,3 ,4,6-tetrahydropyrimido[2, l -a]isoindol 6-01, m.p. 18l3C., as a white crystalline solid which is insoluble in water and soluble in ethanol and dimethylacetamide. 1

Analysis: Ultra Violet Absorption ETOH) max. 234.5 mu (e=12,100), infl. 266 mu (e=4,000); Ultra Violet Absorption (pH 1) max. 240 mu (E -14,000), infl. 266 my. (e==4,000); Infra Red Absorption (KBr) 1640 cm, 2300-3000 cm; Infra Red Absorption of the in situ hydrochloride by the above-identified procedure (KBr) 1670 cm, 2600-3100 cm.

Calcd for C H N O: C, 73.73; H, 8.25; N, 11.47. Found: C, 74.03; H, 7.99; N, 11.63.

6-( 3-Amino-4-ch1orophenyl)-2,3,4,6- tetrahydropyrimido 2, l -a ]isoindol-6-ol, m.p. 227-8C. dec., as a white crystalline solid which is insoluble in water and soluble in hot dimethylacetamide.

Analysis: Calcd for C H N O: C, 77.67; H, 6.52; N, A

10.07. Found: C, 77.62; H, 6.48; N, 9.94.

EXAMPLE V11 When the procedure of the aforementioned Examples is employed, the hereinafter listed 2-(3- aminopropyl)phenylisoindoles are oxidized to afford the following products:

TETRAHYDROPYRIMIDO- lSOlN DOLOLS 2-( 3-aminopropyl )-6chlorol phenylisoindole 2-( 3-aminopropyl-5-methyll-phenylisoindole 2-( 3-aminopropyl )-6-ethylamino- 1 -phenylisoindole 2-( 3-arninopropyl )-5,6-dichlorol-phenylisoindole 2-( 3-aminopropyl-5,6dimethoxyl-phenylisoindolc 2-(3-aminopropyl)-1-(3,4- diiodophenyl )isoindole 2-( 3-aminopropyl l isopropyl -S,6-dipropoxyisoindole 2-( 3-aminopropyl I 3,4- diethoxyphenyl )isoindole phenyl )isoindole 5-amino-2-( 3-aminopropyl) isoindole S-chlorol 4-ethylphenyl) isoinodole 2-( 3-aminopropyl l'( 2- thienyl )isoindole 8-chloro-2,3,4,6-tetrahydro- 6-phenylpyrimido[2, 1 -al isoindol-6-ol 2,3,46-tetrahydro-9-methyl- 6-phenylpyrimido[ 2, l-a] isoindol-6-ol 8-ethylamino-2,3 ,4,6-tetrahydro-6-phenylpyrimido[ 2, 1 -21] isoindol-6ol 8,9-dichloro-2,3 ,4,6-tetrahydro-6-phenylpyrimido[2,1a] isoindol-6-ol 2,3 ,4,6-tetrahydro-8,9- dimethoxy-6-phenylpyrimido [2, l-a]isoindol-6-ol 2,3 ,4,6-tetrahydro-6-( 3 ,4- diiodophenyl)pyrimidol2,1-a] isoindol-6-ol 2,3 ,4,6-tetrahydro-6-isopropyl -8,9-dipropoxypyrimidol 2,1-a] isoindol-6-0l 6-( 3,4-diethoxyphenyl-2,3,4,6 -tetrahydropyrimid0[2,1-a] isoind0l6ol 6-( 4-hexylphenyl )-2,3 ,4,6- tetrahydropyrimidol 2, l-a] isoindol--ol 9-aminn-2,3,4,6-tetrahydropyrimidol 2, l -a ]isoindol 9-chloro6-( 4-ethylphenyl 2.3 ,4,6-tetruhydropyrimido 2,1-a1isoinodol-6-ol 2 ,3 ,4 ,6-tetrahydro-6- (Z-thienyl )pyrimidol 2, 1 -21] isoindol-6-ol 1 7 8-ethylamino-2,3,4,6-tetrahydro-6-phenylpyrimido [2,1-alisoindo1-6-ol dihydrochloride; 8,9-dichloro-2,3,4,6-tetrahydro-6-phenylpyrimido [2,l-alisoindol-6-ol hydrochloride: 2,3,4,6-tetrahydro-8,9-dimethoxy-6-phenylpyrimido [2,l-alisoindol-6-ol hydrochloride; 2,3,4,6-tetrahydro-6-( 3 ,4-diiodopheny1 )pyrimido [2,1-a1isoindol-6-ol hydrochloride; 2-(3,4.5,6-tetrahydro-2-pyrimidinyl)-2-methyl-4,5-

dipropoxypropiophenone hydrochloride; 6-(3,4-diethoxyphenyl)-2,3,4,6-tetrahydropyrimido [2,1-a1isoindol-6-ol hydrochloride; 6-(4-hexylphenyl)-2,3,4,6-tetrahydropyrimido[2,1-

a] isoindol-6-ol hydrochloride;

4-amino-2-( 3 ,4 ,5 ,6-tetrahydro-2 pyrimidiny1)benza1dehyde dihydrochloride;

9-chloro-6-(4-ethylphenyl)-2,3,4.6-

tetrahydropyrimido[2, l -a]isoindol-6-ol hydrochloride;

2,3 ,4,6-tetrahydro-6-(2-thienyl)pyrimido[2,1-a]

isoindol-6-ol hydrochloride;

2,3 ,4 .6-tetrahydro-9-methyl-6-phenylpyrimido[ 2, 1

a] isoindol-o-ol hydrochloride; 1

2,3 .4,o-tetrahydro-6-phenyl-7spropylpyrimido[2, l

a] isoindol-6-ol hydrochloride;

6-( 4-fluorophenyl )-2.3 ,4,6-tetrahydropyrimido[ 2, l-

a] isoindol-6-ol hydrochloride;

6-( 3-bromo-4-methylphenyl )-2,3 ,4,6-

tetrahydropyrimido [2,1-a1isoindol-6-ol hydrochloride; i

2,3 ,4,6-tetrahydro-6-( 3-iodophenyl)pyrimido[ 2, 1 -a] isoindol-6-ol hydrochloride;

9-amyl-2,3,4,6-tetrahydro-6-phenylpyrimido[ 2, 1 -a] isoindol-6-ol hydrochloride;

2,3,4,6-tetrahydro-6-pheny1-8-propylaminopyrimido [2,1-alisoiridol-6-ol dihydrochloride;

9-but0xy-2,3 ,4,b-tetrahydro 6-phenylpyrimido[2, l

a] isoindol-6-ol hydrochloride;

2,3 ,4,6-tetrahydro-6-( 3 ,4-dimethylphenyl )pyrimido [2, 1 -a lisoindol-6-ol hydrochloride;

2,3 ,4,6-tetrahydro-6-( 4-propox-ypher1yl pyrimido[2,l-a] isoindo1-6-ol hydrochloride;

2-( 3,4,5 ,6-tetrahydro-2-pyrimidinyl)4,5-dimethylbenzaldehyde hydrochloride; v

2,3 ,4,6tetrahydro 6-pyridylpyrimido[ 2, l-alisoindol- 6-01 hydrochloride; and l i 2-( 3,4,5 ,6-tetrahydro-2-pyrimidinyl )-4- methoxyvalerophenone hydrochloride.

EXAMPLE X Thirty-five grams of 9b-(p-chlorophenyl)-1,2,3,9btetrahydrol H-imidazo[ 2, 1-a ]isoindol-5.-on'e and 150 ml. of 60 percent hydrochloric acid are.:stirred and heated to a clear solution. Stirring is continued for 20 minutes after solid begins to precipitate. The mixture is cooled and the solid is separated by filtration. On recrystallization from ethanol there is obtained 2-(2- aminoethyl)-3(p-chlorophenyl)-3- hydroxyphthalimidine hydrochloride, m.p. 2435C.

Analysis: Calc'd for C H' N O Crl'HClLC; 56.63; H, 4.76; N, 8.26; Cl, 20.91. Found: C; 5.638; H, 4.57; N, 8.01;Cl, 20.9. i

Seventeen grams of the phthalimidine hydrochloride from above, 20 g. of 'p-toluenesulfon-yl chloride and 200 ml. of pyridine are refluxed'for two hours and then the mixture is evaporated'toxdryne'ss. on recrystallization of the residue from ethanol there is obtained 9b- 18 (p-chloropheny1)- l ,2,3,9b-tetrahydro- 1 -(p-tolylsulfonyl)-1H-imidazo[2,1-a] isoindol-5-one, m.p.

Analysis: Calcd for C H CIN O S: C, 62.93; H, 4.34;'N', 6.38; Cl, 8.08; S, 7.30. Found: C, 63.24; H, 4.61; N, 6.15; Cl, 7.91; S, 7.3.

Ten grams of 9b-(p-chlorophenyl)-l,2,3,9btetrahydro-l-(p-tolylsu1fonyl)-11-l-imidazo[2,1- alisoindol-S-one are dissolved in 25 ml. of percent sulfuric acid and stirred at room temperature for /2 hour. The solution is quenched with ice water, then filtered to separate some precipitated solid. The filtrate which contains the sulfate salt of 4'-ehloro-2-(2- imidazolin-2-y1)benzophenone is cooled and made basic with a saturated sodium bicarbonate solution. The precipitated solid is separated by filtration and washed thoroughly with water. On recrystallization from ethanol there is obtained 5-(4-chlorophenyl)-2,3- dihydro-SH-imidazo [2,l-a]isoindol-5-ol, m.p. 2157C., dec., as a white crystalline solid which is insoluble in water and soluble in ethanol.

Analysis: Ultra Violet Absorption ETOH) max. 223 mp. (e=19,000), infl. 242.5 mp. (F8300), max. 268.5 my. (e=4,400), max. 272 mp. (e=4,400); Ultra Violet Absorption (pH 1) infl. 223 mu (e=l8,000), max. 251 mu (e=11,000), max. 253 my. (e=10,800); Infra Red Absorption (KBr) 1647 cm", 2300-3200 cm".

Caled for C H,;,N OC1:C, 67.49; H, 4.60; N, 9.40; C1, 1245. Found: c, 67.18; H, 4.32; N, 9.68; (:1, 12.7.

In a similar manner, the sulfate salts of 2-(2- imidazolin-2-y1)-3,4-diiodobenzophenone; 2'(2- imidazolin-Z-yl)-2-methyl-4',5'dipropoxypropiophenone and 3,4-diethoxy-2-(2-imidazolin-2- yl)benzophenone are produced which are then contacted with a saturated sodium bicarbonate solution to respectively afford the following compounds: 2,3- dihydro-5-(3,4-diiodopheny1)-5H-imidazo[2,1- a]isoindol-5-ol; 2,3-dihydro-5-isopropyl-7,8- dipropoxy- 5H-imidazo[2,1-a]isoindol-5-ol; and 5-(3,4- diethoxyphenyl )-2,3-dihydro-5Himidazo[ 2, 1 -a] isoindol-5-ol.

EXAMPLE X1 Seventy grams of 9b-(ptolyl)-l,2,3,9b-tetrahydro- 1H-imidazo[2,l-alisoindol-S-one and 300 ml. of 48 percent hydrobromic acid are stirred and heated to a clear solution. Stirring is continued for fifteen minutes after precipitation. Thereafter, the reaction mixture is cooled and the precipitated solid, 2-(2-aminoethyl)-3- (p-tolyl)-3-hydroxyphthalimidine hydrobromide, is separated by decantation, admixed with 40 g. of ptoluenesulfonyl chloride and 400 ml. of pyridine, heated to C. for 4 hours and evaporated to dryness.

Twenty grams of the residue 9b-(p-tolyl)-1,2,3,9btetrahydro-' 1 p-tolylsulfonyl l H-imidazo 2, l alisoindol-S-one are dissolved in 50 ml. of 80 percent sulfuric acid and stirred at room temperature for one hour. The reaction mixture which contains the sulfate salt of 2-( Z-imidazolin-Z-yl)-4-methylbenzophenone is then cooled by the addition of ice water and made alka line by the addition of a 10N sodium hydroxide solution. The precipitated solid is separated by decantation and recrystallized from dioxan to obtain crystalline 2,3- dihydro-5-(4-tolyl)-5H-imidazo[2,l-alisoindol-S-ol, m.p. 208-210C.

In a similar manner, the following sulfates are synthesized: 4'-hexyl-2-(2-imidazolin-2-yl)benzophenone; 4- amino-2-(2-imidazolin-2-yl)benzaldehyde; 4-chloro- 2-(2-imidazolin-2-yl)-2-phenylacetophenone; and 2- (2-imidazolin-2-yl)phenyl-Z-thienyl ketone which are then contacted with a base to respectively afford the following: -(4-hexylphenyl)2,3-dihydro-5H- imidazo[2,1-a]isoindol-5-ol; 8-amino-2,3-dihydro-5H- imidazo l 2 1 -a isoindol-S -ol; 8-chloro-5 4- ethylphenyl )-2,3-dihydro-5H-imidazo[2, 1 -a]isoindol- 5-01; and 2,3-dihydro-5-(2-thienyl)-5H-imidazol2,1- a]isoindol-5-ol.

EXAMPLE Xll Thirty-five grams of 9b-phenyl-1,2,3,9b-tetrahydrolH-imidazo[2,l-alisoindol-S-one and 150 ml. of 50 percent hydrochloric acid are stirred and heated to a clear solution. Stirring is continued for 30 minutes after solid begins to precipitate. The mixture is cooled and the solid is separated by filtration. On recrystallization from ethanol there is obtained 2-(2-aminoethyl)-3- phenyl-3-hydroxyphthalimidine hydrochloride.

Seventeen grams of the phthalimidine hydrochloride from above, g. of p-butoxyphenylsulfonyl chloride and 200 ml. of pyridine are refluxed for two hours and then the mixture is evaporated to dryness. On recrystallization of the residue from ethanol there is obtained 9b-phenyll ,2,3 ,9b-tetrahydro- 1 -(p-butoxyphenylsulfonyl)-lH-imidazo [2,l-alisoindol-5-one which is admixed with ml. of 95 percent sulfuric acid for one hour. The reaction mixture which contains the sulfate salt of 2-(2-imidazolin-2-yl) benzophenone is then cooled by the addition of ice water and made alkaline by the addition of a 5N potassium hydroxide solution. The product is then separated by filtration and recrystallized from dioxan to afford 2,3-dihydro-5-phenyl-- 5H-imidazo[2,l-a]isoindol-5-ol, m.p. 207C., as a white crystalline solid which is insoluble in water and soluble in dimethylacetamide and ethanol.

Analysis: Ultra Violet Absorption (95% ETOH) infl. 225 mp. (e=14,900), max. 268 my (e=4,200); Ultra Violet Absorption (pH 1) max. 250 mp. (=13,500); lnfra Red Absorption (KBr) 1660 cm, 2300-3000 cm".

Calcd for C H N O: C, 76.77; H, 5.63; N, 11.20. Found: C, 76.63; H, 5.66; N, 11.0.

Similarly, the sulfate salts of 2-(2-imidazolin-2-yl)-4- methylbenzophenone and 2-(2-imidazolin-2-yl)-6- propylbenzophenone are produced which are then converted to 2,3-dihydro-8-methyl-5-phenyl-5H- imidazo[2, 1 -a]isoindol-5-ol and 2,3-dihydro-5-phcny1- 6-propyl-5H-imidazo[2,1-a]isoindol-5-ol.

EXAMPLE Xlll Forty grams of 9b-(p-bromophenyl)-l,2,3,9btetrahydro-1H-imidazo[2,1-a]isoindol-5-one and 200 ml. of 50 percent hydrochloric acid are stirred and heated to a clear solution. Stirring is continued for 20 minutes after solid begins to precipitate. The mixture is cooled and the solid is separated by filtration. On recrystallization from ethanol there is obtained 2-( 2- aminoethyl)-3-(p-bromophenyl)-3- hydroxyphthalimidine hydrochloride.

Twenty grams of the phthalimidine hydrochloride from above, 24 g. of p-bromophenylsulfonyl chloride and 250 ml. of pyridine are refluxed for three hours and then the mixture is evaporated to dryness. On recrystallization of the residue from methanol there is obtained 20 9b-(p-bromophenyl)-l ,2,3,9b-tetrahydro-1-(pbromophenylsulfonyl)-1H-imidazo[2,1-a]isoindol- 5-one which is hydrolyzed with sulfuric acid to afford the sulfate salt of 4'-bromo-2-(2-imidazolin-2- yl)benzophenone which is contacted with an aqueous sodium hydroxide solution. The product is then separated by filtration to afford 5-(4-bromophenyl)-2,3- dihydro-5H-imidazo[ 2, l -a]isoindol-5-ol, m.p. 194-6C., as a white crystalline solid which is soluble in dimethylacetamide and hot ethanol.

Analysis: Ultra Violet Absorption (95% ETOH) max. 228 mu (e=15,300), max. 268 my. ('=4,800), max. 274 my. (e=4,800); Ultra Violet Absorption (pH 1) max. 250 my. (e=l 1,000), max. 270 mp. (=l0,500); Infra Red Absorption (KBr) 1660 cm, 2300-3000 cm.

Calcd for C H N OBr: C, 58.38; H, 3.98; N, 8.50; Br, 24.28. Found: C, 58.25; H, 4.02; N, 8.46; Br, 24.00.

In a similar manner, the following compounds are prepared:

3 ',4'-dichloro-2-( 2-imidazolin-2-y1 )benzophenone sulfate which is neutralized to afford 5-(3,4- dichlorophenyl)2,3-dihydro-5H-imidazo[2,1- v alisoindol-S-ol, m.p. 20 3-5C., as a white crystalline solid which is soluble in hot dimethylacetamide and hot 'ethanol.

Analysis: Ultra Violet Absorption (95% ETOH), infl. 228 mp. (e=21,200), max. 274 my. (e=4,500), max. 281 mu (e=3,500); Ultra Violet Absorption (pH 1) max. 243 my. (e=12,200), max. 251 mp. (e=l 1,750), infl. 265 mp. (=9,000), infl. 278 mp. (e=6,750); Infra Red Absorption (KBr) 1655 cm", 2300-3000 cm".

Calcd for C H CI N O: C, 60.21; H, 3.79; N, 8.78; Cl, 22.22. Found: C, 59.91; H, 3.66; N, 8.66; CI, 22.30.

4-fluoro-2-( Z-imidazolin-Z-yl)benzophenone sulfate which is neutralized to afford 5-(4-fluorophenyl)-2,3- dihydro-5H-imidazo[ 2, 1 a lisoindol-S-ol, m.p. 2 l4-2l6C., dec., as a white crystalline solid which is insoluble in water and soluble in dimethylacetamide.

Analysis: Ultra Violet Absorption (95% ETOH), infl. 235 mu (=12,000), infl. 242 my. (e=10,200), max. 263 mp. (e=6,l00), max. 268 mp. (e=5,600); Ultra Violet Absorption (pH 1) max. 251 (e=13,000);.lnfra Red Absorption (KBr) 1640 cm", 2300-3000 cm.

Calcd for c,.,H, ,N,oF: C, 71.62; H, 4.88; N, 10.44. Found: C, 71,73; H, 5.00; N, 10.68.

3'-bromo-4-methyl-2-( 2-imiadzolin-2- yl)benzophenone sulfate which is neutralized to affor 5-(3-bromo-4-methylphenyl)-2,3-dihydro-5H- imidazo[2,l-ajisoindol-S-ol, m.p. 233-5C., dec., as a white crystalline solid which is insoluble in water and soluble indimethylacetamide. 5

Analysis: Calcd for C, H, BrN O: C, 59.47; H, 4.41; N, 8.16; Br, 23.28 Found: C, 59.75; H, 4.60; N, 8.32; Br, 23.23.

EXAMPLE XlV recrystallization from ethanol there is obtained g. of

9b-phenyll ,2,3 ,Qb-tetrahydrol -(p-tolyls ulfonl )-5H- imidazol 2, lalisoindol-S-one, m.p. 158-l 60C.

Ninety grams of the above prepared sulfonamide compound is dissolved in 200 ml. of 80% sulfuric acid and is left at room temperature for 2 hours. The solution is diluted with two volumes of water and extracted with ether. The aqueous portion which contains the sulfate salt of 2-(2-imidazolin-2-yl)benzophenone is then neutralized with 50% sodium hydroxide solution while keeping the temperature below 25C. The solid is separated and washed with water. On'recrystallization from dimethylformamide there is obtained 27 g. of 2,3- dihydro-phenyl-5 H-imidazo [2, l -a ]isoindol-5-ol which has the same analytical characteristics as the product of Example Xll.

EXAMPLE XV Sixty grams of 9b-(4-chlorophenyl)-l,2,3,9btetrahydro-5H-imidazo2,l-alisoindol 5-one, 60 g. of p-toluenesulfonyl chloride and 750 ml. of pyridine are heated at reflux for fourteen hours. The reaction mixture is worked-up as described in Example XIV to obtain 70 g. of 9b-(p-chlorophenyl)-l,2,3,9b-tetrahydro- 1-(p-tolylsulfonyl)-5-H-imidazo [2,1-a]isoindol-5-one, m.p. l69171C. which can be recrystallized from ethanol (m.p. 170-2C.)

Forty-five grams of the above prepared sulfonamide compound is dissolved in 100 ml. of 80% sulfuric acid and is left at room temperature for 2 hours. The solution is diluted with two volumes of water and extacted with ether. The aqueous portion which contains 4- chloro-2-(2-imida2olin2-yl)benzophenone is neutralized with 50% sodium hydroxide solution while keeping the temperature below 25C. The solid is separated, washed with water and recrystallized from dimethylformamide to afford 23 g. of 5-(4-chlorophenyl)-2,3- dihydro-SH-imidazol2,1-a1isoindol-5-ol which has the same analytical characteristics as the product of Example X.

The above procedure is repeated to react a l,2,3,9btetrahydro-lH-imidazol2,l-alisoindol-S-one of V111- XlI with an appropriate sulfonyl halide, in pyridine, at a temperature within the range of about 80C. to above l C. for a period of about 2 to about 10 hours to afford the corresponding sulfonamide which is treated with about 80 to about 100 percent sulfuric acid to yield an appropriate 2( 2-imidaZolin-2- yl)benzophenone sulfate which is neutralized to produce a 2.3-dihydro-5H-imidazo[2,l-a]isoindol-5-ol.

EXAMPLE XVl Ten grams of 2,3-dihydro-5-phenyl-5Himidazo{2,1- a]isoindo1-5-ol, as described in Example XII, are suspended in 75 ml. of absolute ethanol and then saturated with a continuous flow of hydrochloric acid gas. The resulting solution is filtered to remove impurities and on standing 2-(2-imidazolin2-yl)benzophenone hydrochloride precipitates as a white crystalline sold, m.p. l979C., dec.

Analysis: Ultra Violet Absorption (95% ETOH) max.

DIHYIiR OIMIDAZOISOINDOLOLS 250 mu(e=12,800); Infra Red Absorption (KBr) 1647 'cm, 2400-3200 cm.

Calcd for C H N- O.HCl: C, 67.03; H, 5.27; N, 9.77; Cl, 12.36.

Found: C, 66.88; H, 5.33; N, 9.83; CI, 12.50.

EXAMPLE XVII Ten grams of 5'(4-chlorophenyl)-2,3-dihydro-5H- imidazo-[2,l-a]isoindol-5-ol, as described in Example X, are suspended in ml; of absolute ethanol and then saturated with a continuous flow of hydrochloric acid gas. The resulting solution is filtered, evaporated to dryness and the residue recyrstallized from ethanolethyl acetate to afford 4'-chloro-2-(2-imidazolin-2- yl)benzophenone hydrochloride, m.p. l70-2C., dec., as a white crystalline solid which is soluble in water.

Analysis: Ultra Violet Absorption ETOH) infl. 223 m,u.(e=19,100), max. 252 mp. (e -12,100), max. 265 mp. (e=12,300); Infra Red Absorption (KBr) 1647 cm, 2300-3200 cm.

Caled for C H N OCLHC1: C, 59,80; H, 4.40; N, 8.72; CI, 22.08.

Found: C, 59.63; H, 4.50; N, 8.72; Cl, 21.79.

Similarly, the following hydrochlorides are prepared:

2-(2-imidazolin2-yl)-3,4-diidobenzophenonehydrochloride;

2-( 2-imidazolin-2-yl )-2-methyl-4' ,5 '-dipropoxypropiophenone hydrochloride;

3 ',4'diethoxy-2-( 2-imidazolin-2-yl) benzophenone hydrochloride;

2-(2-imidazolin-2-yl)-4'-methylbenzophenone hydrochloride;

4'-hexyl-2-(2-imidazolin-2-yl)benzophenone hydrochloride;

4-amino-2-( 2-imidazolin-2-yl)benzaldehyde dihydrochloride;

EXAMPLE XVIII When the procedure of Examples X XV are repeated with appropriate starting material, the following dihydroimidazoisoindolols are prepared which by the procedure described in Examples XVI XVII are then converted to their corresponding imidazolinyl phenyl carbonyl hydrochlorides.

IMIDAZOLINYL PHENYL CARBONYL HYDROCHLORIDE 7-bromo-2,3-dihydro-5-( 4-tolyl) -5H-imidazo[2.1-a]isoindol-5-ol 2,3-dihydro-X-methyLS-pmpyI- 5H-imidazo[2,1-alisoindol-S-ol hexahydro-2,5-benzodiazocine dihydrochloride are dissolved in 50 ml. of water. A solution of l g. of potassium permanganate in 50 ml. of water is added dropwise over a period of one-half hour. The mixture is filtered to remove inorganic salts and the filtrate is made basic with sodium carbonate solution. The precipitated solid is separated and washed with water. On recrystallization from ethanol there is obtained 5-(4- chlorophenyl)-2,3-dihydro-5H-imidazo [2,lalisoindol-S-ol which has the same physical characteristics as the identical compound of Example X.

Similarly, 2,3-dihydro-5-(2-phenethyl)-5H-imidazo [2,l-alisoindol-5-ol is obtained by the oxidation of 1- phenethyll ,2,3 ,4,5 ,6-hexahydro-2,S-benzodiazocine dihydrobromide with potassium dichromate.

EXAMPLE XXI Repeating the procedure of Example XX to oxidize a hereinafter listed hexahydrobenzodiazocine, the following dihydroimidazoisoindolol compounds are prepared:

HEXAHYDROBENZODIAZO CINE DIHYDROIMIDAZO ISOINDOLOLS l,2.3,4.5,6-hexahydro-l-(pbromophcnyl )-2,5-henzodiazocinc dihydruchloride l,2,3.4,5,6-hexahydro-l-(pmethoxyphenyl )-?.,5-benzodiamcinc dihydrochloridc l -benzyl- 1 2.3.45 .6-hexahydrd-Qj-henzodiazocine dihydrobromide l,2,3.4.5.6-hexahydro-l-(2- thie nyl )-2,S-bcnzodiazocine dihydrochloride hcxahydro-2,S-benzodiazocine dihydrochloride l 2,3,4 5.6-hexahydro-8- methyl- 1 -phenyl-2.5-benzdiazoeinc dihydrochloridc l,2,3,4,5,6-hexahydro-l- (Z-pyridyl )-2,5bcn7.odiazocine dihydrochloride l2,3,4.5,6hexahydro-8,9 dimcthoxy l p-tolyl )2 5- benzodiazocine dihydro- 4hromophenyl-2,3-dihydro- SH-imidazol 2.1-1: Iisoindol- 5-ol Z .3-dihydro-5-( 4-methoxyphenyl )-5H-imida7.ol 2, l-al isoindol-S-ol 5-henzyl-2,3-dihydro-5H- imidazol 2,1-alisoindol-5-ol 2,B-dihydro-7-methyl-5-phenyl -5H-imidazol 2, l -a]isoindol- 5 ol 2,3-dihydro-5-( 2-pyridyl 5H-imidazo| 2, I -a]isoindol- 5-ol 2,3-dihydro 7,8-dimethoxy- 5-(4-tolyl)-5H-imidazol2,1-a] isoindoLS-ol chloride EXAMPLE XXII EXAMPLE XXIII One gram of l,2,3,4,5,6-hexahydro-b l-phenyl-2,5- benzodiazocine dihydrochloride is dissolved in ml. of water. A solution of 0.5 g. of potassium permanganate in 25 ml. of water is added over a period of one hour. The mixture is filtered to remove precipitated inorganic salts and the filtrate is made alkaline with a potassium bicarbonate solution. The precipitated product is separated and recrystallized from ethanol. The product obtained in this manner is 2,3-dihydro-5-phenyl- 5H-imidazo[2,1-a]isoindol-5-ol which has the same physical characteristics as the identical compound of Example XII.

In the same manner, l,2,3,4,5,6-hexahydro-1-(2,4- dimethoxyphenyl)-2,5-benzodiazocine is converted to 2,3-dihydro-5-(2,4-dimethoxyphenyl)-5I-I- imidazo[2, l -a]isoindol -5-ol.

EXAMPLE XXIV HEXAHYDROBEN- ZODIAZOCINES DIHYDROIMIDAZOISOINDOLOLS 1,2,3 .45 ,6-hexahydro- 1 5 ,6- 7,X-tetrahydro-Z-naphthyl 2,5-benzodiazocine 1.2.3.4,5 ,o-hexahydrol -(ptrifluoromethylphenyl )-2,5- benzodiazocine l,2,3.4,5 ,6hexahydro8.9- dichlorol -phenyl-2,5- bcnzodiazocine l-(p-ethylphenyl )-1 2.3.4- 5 ,6-hexahydro-2,5 -benzodiazocinc 8,9-dibromol .2,3,4,5.6- hexahydrol phenyl 2,5- benzodiazocine l ,2 3,4,5,6hexahydro-9- methylaminol p-tolyl 2 ,5benzodiazocine 2,3-dihydro-5-(5,6,7,8- tetrahydro-Z-naphthyl )5H- imidazol 2, l-alisoindol-S-ol 2,3-dihydro-5H-imidazo [2, l -a ]isoindol-5 ol 7,8-dichloro-2,3-dihydro S-phenyl-SH-imidazol 2, l -a] isoindol-5 ol 5-(4'ethylphenyl )-2,3-dihydro'5 H-imidazo[ 2,1-a] isoindol-5ol 7,8-dibromo-2,3-dihydro S-phenyl-S H-imidaz0[ 2, l -a] isoindol-S-ol 2,3-dihydro-8-methylamino- 5-( 4-tolyl )-5H-imidazo EXAMPLE XXV Ten grams of l-(3,4-dichlorophenyl)-l,2,3,4,5,6- hexahydro-2,5-benzodiazocine dihydrochloride dissolved in 250 ml. of water. A solution of 5.0 g. of potassium permanganate in 250 ml. of water is added over a period of two hours. The mixture is filtered to remove precipitated inorganic salts and the filtrate is made alkaline with a sodium bicarbonate solution. The precipitated product is separated and recrystallized from methanol. The product obtained in this manner is 5- (3,4-dichlorophenyl)-2,3-dihydro-5I-I-imidazo[2,1- alisoindol-S-ol which has the same physical characteristics as the identical compound of Example XIII.

Similarly, l-(3,4-dibromophenyl)-1,2,3,4,5,6- hexahydro9-methyl-2,S-benzodiazocine dihydrobromide is oxidized to afford 5-(3,4-dibromophenyl)-2,3- dihydro-8-methyl-5 H-imidazo 2, l -a]isoindol-5-ol.

EXAMPLE XXVI HEXAHYDROBEN- ZODIAZOCINES Dll-IY DROIM IDAZOISOINDOLOLS l-(p-cthoxyphenyU-l 2,3,4. 5 ,6-hexahydro-2 ,5- bcnzodiuzo- 2.3-dihydro- .8-dimethyl SH-imidazol 2, l -a]isoindol -5-ol 7-ethyl-2,3-dihydro-S-phenyl -5H-imidazo[ 2,1-alisoindol -5-ol l,2,3,4,5 ,-hexahydro-l ,9- dimethyl-2,5 -benzodiazocine S-ethyll .2 ,3 .4,5,6-hexahydro l -phenyl-2,5-benzodiazocine l,2,3,4,5,6-hexahydro-8,9- dimethyll -phenethyl-2,5- benzodiuzocine 8-fluorol ,2,3,4,5,6hexahydrol ptolyl )-2.5- bcnzodiazocinc What is claimed is: l. A process for the preparation of a compound having the formula:

wherein R is selected from the group consisting of hydrogen, lower alkyl, phen(lower)alkyl, phenyl, monohalophenyl, dihalophenyl, mono(lower)alkylphenyl, di(lower)alkylphenyl, trifluoromethylphenyl,

28 mono(lower)alkoxyphenyl, di(lower) alkoxyphenyl, thienyl, pyridyl, fury] and tetrahydro-Z-naphthyl; R is selected from the group consisting of hydrogen, halogen, amino, lower alkylamino, lower alkyl and lower alkoxy; wherein said lower alkyl and said lower alkoxy have from one to six carbon atoms and R is hydrogen when R and R are dissimilar; and when R and R are the same they are both selected from the group consisting of hydrogen, halogen, lower alkyl and lower alkoxy wherein said lower alkyl and said lower alkoxy have from one to six carbon atoms which comprises the step of contacting a compound selected from the group consisting of those having the formula:

dizing agent is gaseous oxygen.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 2 3 98 231 Page 1 0f 2 DATED August 5, 1975 INVENTOR(S) Sulkowski it is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 35: imidazoline portion of structure is incorrect. Should be:

Column 4, line 30: structure 2 should be:

- CH CH NH Column 8, line 50: imidazoline ring of structure is lacking an NH group. Should be:

' UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,898,231 Page 2 of 2 DATED August 5, 1975 v Q INVENTOR(S) I sulkOwski It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 6, line 60: structure (b) is not complete. Should be:

Signed and Scaled this Twenty-seventh Day of February I979 [SEAL] Arrest:

RUTH C. MASON DONALD W. BANNER Arresting Ojficer Commissioner of Patents and Trademarks D 

1. A PROCESSFOR THE PREPARTION OF A COMPOUND HAVING THE FORMULA.
 2. A process as described in claim 1 wherein the oxidizing agent is gaseous oxygen. 